DESCRIPTION: Ovarian cancer is one of the major causes of death for women in the United States. Overexpression of the HER-2/neu oncogene has been reported to correlate with poor prognosis for ovarian cancer patients. Therefore, HER-2/neu may be an excellent target for novel anti-cancer agents, particularl those cancers with overexpression of HER-2/neu. The applicant's experimental results indicate that PEA3, a transcriptional factor from the ETS family, represses HER-2/neu transcription in HER-2/neu-overexpressing cancer cells, an that PEA3-liposome complexes may inhibit tumor growth in an animal model of ovarian cancer. The applicant has hypothesized, therefore, that PEA3, through repression of HER-2/neu, may function as a tumor suppressor for HER-2/neu-overexpressing ovarian cancer cells. The long-term goal of the proposed work is to understand the molecular mechanisms by which PEA3 suppresses tumor growth and to develop novel approaches to the treatment of HER-2/neu-overexpressing ovarian cancer cells. The following five specific aim are proposed: 1) to confirm that PEA3 mediates tumor suppression and to determine whether it mediates repression as a result of inhibiting HER-2/neu expression. 2) To investigate the mechanisms and sequences necessary for PEA3 inhibition of HER-2/neu. 3) To examine the preclinical therapeutic effects of PEA3. 4) To test potential synergistic effects of PEA3 gene therapy and chemotherapy for ovarian cancer cells with HER-2/neu overexpression. 5) To design expression vectors for preferential expression of PEA3 in HER-2/neu-overexpressing ovarian cancer cells.